Pathology

Cyanocobalamin (Vitamin B12) is one of a family of cobalamins consisting of 1) a corrin ring around a cobalt atom and 2) a nucleotide group of a base (5,6-dimethylbenzimidazole) and a phosphorylated ribose with 1-amino,2-propanol. This complex is linked to a ß-group.

The ß-group is:

cyanide in cyanocobalamin (at right),
an adenosyl group in adenosylcobalamin,
a methyl group in methylcobalamin,
and a hydroxyl group in hydroxocobalamin.

Conversion between forms readily takes place in body tissues.

Cobalamin is synthesized exclusively by bacteria. Cobalamin is temporarily bound to R-binding proteins, but released by duodenal digestive enzymes. The newly freed cobalamin is bound by intrinsic factor (IF) secreted by gastric parietal cells.

This IF-cobalamin complex binds to receptors on the brush border of the ileal mucosa and is absorbed over a period of several hours.

Most absorbed cobalamin (90%) is transfered to transcobalamin II, the primary transport protein of cobalamin.

Total body stores of cobalamin measure 2-5 mg. The average daily diet in the US contains about 5-30 mg, where as daily requirements are only 2-5 mg/day.

Cobalamin, in the form of adenosylcobalamin, is stored primarily in the liver.

Adenosylcobalamin is key to conversion of methylmalonyl CoA to succinyl CoA (Krebs cycle).

Methylcobalamin is an essential part of the folate-cobalamin reaction necessary for DNA synthesis.

Folic acid (pteroyl monoglutamic acid) occurs in nature as relatively insoluble aggregates - polyglutamates.

Leafy vegetables (broccoli,spinach,asparagus,lettuce), fruit, milk, eggs, liver, and yeast contain folic acid. Some intestinal bacteria also form folic acid.

The average US diet contains about 1,000 mg of folate. The daily requirement is 100-200 mg/day and body stores average 5,000mg. Additional folate is required during pregnancy and growth.

Liver is a major storage site, but releases folate only into the bile for reaborption in the jejunum and ileum. This process, refered to as the enterohepatic circulation, is necessary for maintainance of plasma folate levels. Alcohol interferes with the enterohepatic circulation of folate and can lower plasma folate levels within hours.

Folate is absorbed in the proximal jejunum and ileum although the mechanism is unclear. Conjugases along the brush border break polyglutamates into monoglutamates for absorption.

Folate circulates free or albumin bound in the plasma as N5-methyl FH4.

Absorbed N5-methyl FH4 hands off a methyl group to synthesize methionine from homocysteine in a step requiring cobalamin and generates FH4 (tetrahydrofolate) which is reconjugated to N5,10-methylene FH4 or other FH4-(Glu)n for use in thymidilate and purine synthesis.